From Lewis S Blevins, Jr. M.D. – Long-term follow-up of patients with pituitary disorders is essential for many reasons. Firstly, those patients who have been rendered disease-free are always at risk for recurrence. While long-term remission is the norm, recurrences are seen in between eight and 25% of patients who have had pituitary surgery. Recurrence rates vary depending on the disease, type, invasiveness of the tumor, and the skill and experience of operating neurosurgeons. It is not unusual to develop pituitary hormone deficits within the first couple of years after surgery. A follow-up evaluation will allow the detection of these new deficiencies and enable appropriate treatment.
Further, those patients on hormone replacement require regular assessment because as one age, starts different medications that may affect hormone replacement, and has changes in body weight leading to a change in the volume of distribution of drugs, dose requirements will indeed change. Some patients require treatment for disorders of hormone overproduction by their pituitary tumors. These patients require careful follow-up and drug adjustments to ensure optimal therapy. Lastly, some treatments, like surgery and radiotherapy, may be associated with developing hypopituitarism and other consequences of therapy that require periodic monitoring and potential treatment.
There are innumerable reasons to choose a Pituitary Center of Excellence for long-term care. Clearly, geographic proximity to a Center of Excellence is a luxury. Many patients are, therefore, evaluated and managed by their local endocrinologists and, in some cases, their primary care physicians. The advent of and widespread use of telemedicine has enabled some patients to stay in contact with their treating physicians at pituitary centers, who can co-manage patients with their local doctors. Some patients have had an excellent postoperative course, have a low risk of recurrence or even straightforward hormone deficits, and do not require ongoing services at a Pituitary Center. For these patients, it makes sense that their local endocrinologists or primary physicians follow them.
At the University of California, San Francisco, we have developed a series of recommendations for patients followed by their primary care physicians and local endocrinologists. These recommendations focus on recommended surveillance and advise when to refer patients back to our center for evaluation. They pertain to those patients who do not have complex situations that require us to stay involved in their ongoing evaluation and management.
Pituitary World News is delighted to post these recommendations so patients can share them with their families and treating physicians at the discretion of our followers, depending on their relevant clinical situation.
Prolactinoma: Successful surgery
Your patient underwent successful surgery for a prolactinoma. This document aims to provide information regarding similarly treated patients at our institution and recommendations for long-term follow-up.
Generally, we expect patients to remain in long-term remission. We don’t often use the term “cure” because of the ever-present risk of recurrent disease. For patients with microadenomas, about 5% of patients will develop a recurrence during their lifetime. For patients with macroadenomas, recurrences are seen in 20 to 30% of patients. A recurrence usually implies that there were microscopic cells left behind at the time of surgery and that the cells were able to recruit the growth and development of a vascular system and then multiply, forming a new tumor deposit. Most recurrences will develop in the first five years after surgery. We have seen late recurrences up to 15 years or more after initially successful surgery. Thus, we recommend lifetime follow-up.
We recommend serum prolactin levels at six-month intervals for two years and then annually after that. Further, any clinical manifestations related to hyperprolactinemia, such as hypogonadism in men, irregular menses, amenorrhea, and galactorrhea in women, should prompt reassessment. Elevated levels should be confirmed by repeat assay. Elevated levels without any clinical manifestations should prompt a macro prolactin assay assessment, and attention should be directed to the free prolactin rather than the total prolactin level.
We consider persistently elevated levels above 30 ng/mL to be clinically relevant but are sometimes concerned about levels between 20 and 30 ng/mL. Typically, levels of this degree would require some consideration of an MRI, while levels above 40 almost always prompt a repeat MRI study. If an MRI is deemed necessary, we recommend a pituitary protocol MRI of the sella rather than an MRI of the brain. Otherwise, patients are not required to have periodic MRI studies to assess tumor presence when prolactin levels remain normal.
Please feel free to contact us anytime if you have questions about your patient. Thank you for the referral and for allowing us to partner with you in the management of this interesting patient.
Prolactinoma: Persistent disease after surgery
Your patient underwent surgery for a prolactinoma. This document aims to provide information regarding similarly treated patients at our institution and recommendations for long-term follow-up.
While most patients are rendered disease-free after prolactinoma surgery, some patients have persistent or recurrent disease. This may be in the form of the obvious disease recognized on the postoperative MRI or microscopic disease wherein the prolactin is elevated despite gross total tumor resection as evidenced by no obvious tumor on MRI.
When the prolactin level remains elevated after surgery, we recommend measuring a macro prolactin level and paying attention to the free prolactin level. If it remains elevated, this suggests the possibility of residual disease and a need for medical treatment.
The main goals of treatment of residual and recurrent hyperprolactinemia include:
- Normalization of the prolactin level.
- Control of any residual tumor.
- Prevention of growth of microscopic tumor.
- Resolution of the manifestations of hyperprolactinemia.
These goals of therapy are often achieved with treatment with dopamine agonist drugs. We prefer the use of cabergoline 0.25 mg once to twice weekly to start with. We check the prolactin level after eight weeks of therapy and then titrate the dose upwards as necessary at 8-week intervals to normalize the prolactin level. Some patients require twice-weekly treatment. Most patients can be controlled with under 1.5 mg twice weekly, but occasional patients with invasive prolactinomas require higher doses. Generally speaking, our goal of therapy is to result in a normal prolactin level. We tend to treat more aggressively and suppress prolactin levels to less than 10 ng/mL in patients with invasive or larger residual tumors. Women attempting to achieve pregnancy probably should be maintained at a serum prolactin concentration between 12 and 17 ng/mL.
Some patients also require sex steroid hormone replacement despite normal prolactin levels because their tumors have damaged the pituitary gland. It is important to remember that estrogens may promote the growth of prolactinomas, so prolactin levels should always be rechecked in patients who start estrogen supplementation. Likewise, in men with hypogonadism treated with testosterone, the testosterone can be aromatized to estrogen and promote the growth of a prolactinoma or failure of dopamine agonist drug therapy. In both of these settings, we increase the dose of cabergoline to again normalize the prolactin concentration.
In patients with obvious or invasive tumors, we usually recommend assessment of MRI studies annually for 2 to 3 years and then periodically after that to ensure that their tumor does not increase in size despite treatment. In patients with hyperprolactinemia but no obvious tumor, we recommend MRI studies less regularly and, based on experience, believe that it is worth repeating the imaging studies at least every 3 to 5 years for evidence of obvious tumor growth. Further, in patients with bouts of extended noncompliance, it is best to reassess whenever the prolactin level rises significantly to determine if additional surgery or radiotherapy is required.
For women with a history of residual or recurrent prolactinoma requiring medical treatment who become pregnant, we recommend referral to our practice for follow-up and management during pregnancy.
For patients who have received radiotherapy for residual and recurrent prolactinoma, we recommend referral to our practice for long-term follow-up to assess for consequences of radiotherapy and decisions regarding discontinuation of cabergoline.
It is rare to be able to successfully discontinue cabergoline in patients with residual or recurrent disease. However, a few patients have enjoyed a drug holiday for several months and even up to a couple of years after five years of therapy. We would be happy to reevaluate patients to determine whether it is reasonable to discontinue treatment in these chronically treated patients.
We would be delighted to partner with you if you would like us to participate in the ongoing long-term management of these patients requiring additional therapy after surgery. Please let us know how we can be of assistance.
Rathke’s Cleft Cyst: Successful surgery.
Your patient underwent successful surgery for Rathke’s cleft cyst. The purpose of this document is to provide you with information and recommendations regarding expectant, long-term follow-up.
These benign cysts may recur in 8 to 12% of patients. Those patients with infected cysts are more likely to have recurrences. Most of the recurrences occur within the first five years of surgery, but we have seen recurrences in patients delayed as long as 15 years after the initial surgery. Thus, these patients require lifetime follow-up for their pituitary condition.
We recommend pituitary protocol MRI studies with and without contrast of the sella annually for three or so years after surgery. Then, if there are no new developments, one may proceed with imaging every couple of years for a few intervals. After that, imaging studies can be obtained every five years. Any new onset visual difficulties, headaches, or new pituitary hormone deficits should immediately prompt an MRI scan regardless of the schedule.
We recommend that patients with any definite or probable recurrences be referred back to us for evaluation.
While some patients may be deficient in one or more anterior pituitary hormones before and after surgery, others may be normal. Regardless, all are at risk for developing delayed hypopituitarism, although this is unusual with Rathke’s cleft cysts. We define hypopituitarism as a partial or complete deficiency of one or more anterior pituitary hormones. We see this delayed hypopituitarism occasionally and believe it’s worthwhile to check pituitary functions annually for 2 to 3 years. The cause is unknown, but new anterior pituitary hormone deficiency states have been known to herald a recurrent cyst.
We appreciate the opportunity to partner with you to manage your patients. Please do not hesitate to contact us with any questions or concerns.
Acromegaly: Successful surgery
Your patient underwent successful surgery for acromegaly.
Recurrences in acromegaly are difficult to understand but seem largely related to tumor size and invasiveness. Generally, 5 to 10% of microadenoma patients and 15 to 30% of macroadenoma patients may develop recurrent disease after being deemed in remission. Thus, it is important to follow these patients indefinitely.
Biochemical features of recurrent disease often precede radiographic evidence of recurrent tumors. Being in remission is usually defined as having a postoperative GH level of less than 1 ng/mL and a normal age and sex-matched IGF-I level. Recurrences have suggested a rise in GH to above 1 ng/mL and an elevation in IGF-1. Patients with recurrent symptoms of acromegaly and a rise in but a normal IGF-I level may have early recurrent disease. Most patients will fail the glucose suppression test in that they do not suppress their GH to less than 0.4 ng/mL after oral glucose.
We recommend checking GH and IGF-I levels at six-month intervals for 2 to 3 years and then annually after that for patients who seem to be in remission after surgery. Of course, the development of symptoms of GH and IGF-1 excess in between these assessments would prompt testing sooner rather than later.
We usually recommend a follow-up MRI of the pituitary one year after surgery and only afterward if the IGF-I and GH are elevated or if the patient fails the glucose suppression test.
If you have any questions or are concerned that the patient might have recurrent disease, please feel free to contact us or refer the patient for reevaluation. Thank you for allowing us to partner with you in your patient’s care.
Cushing’s: Succesful surgery
Your patient underwent successful surgery for Cushing’s Disease.
Nearly all patients in remission will have a period of central adrenal insufficiency lasting from 6 to 18 months after successful surgery. The longer the period of adrenal insufficiency, the more likely the patient will remain in long-term remission. The adrenal insufficiency is caused by suppression of the normal ACTH-producing cells during the period of hypercortisolism. When the offending tumor is removed, there is no longer drive for cortisol production by the adrenal glands, so cortisol levels fall and remain low until the suppressed ACTH-producing cells recover from the suppression and begin to function.
Shorter recovery times may imply that the patient has recurrent disease. Recurrences occur in 5 to 10% of patients with microadenomas and 15 to 35% with macroadenomas. Most recurrences occur within the first five years, but we have seen recurrences as late as 28 years after successful initial surgery, followed by biochemical evidence of remission. In recurrent patients, their cortisol levels normalize and then slowly increase through the normal range to become elevated over time. Patients suspected of having recurrence can be identified by assessment of the late-night salivary cortisol and an overnight 1 mg dexamethasone suppression test. Most of them will have normal 24-hour urine cortisol excretion rates during the early parts of recurrence. We notice, however, that in many of these patients, the urine cortisol has risen through the normal range. Some of the earliest symptoms and signs of recurrence include weight gain and insomnia. Most patients will seek attention believing their Cushing’s has recurred before their physicians even suspect the disorder.
Some of our patients are discharged from the hospital, taking double the usual steroid dose. We usually like for them to be on replacement doses of steroids by six weeks after surgery. Replacement steroid dose equivalents that you might see used include dexamethasone 0.25 mg at bedtime or hydrocortisone 10 to 20 mg in the morning and 5 to 10 mg in the evening.
We recommend postoperative assessments at six weeks. Typically, we suggest the patient hold their dexamethasone or hydrocortisone for 24 to 36 hours and then have ACTH and cortisol levels at 8 AM or early during the patient’s usual morning time. This process is usually repeated at 2 to 3-month intervals until the patient shows ACTH and cortisol secretion recovery.
A rise in the morning cortisol to 7 µg/dL or greater on one of these regular assessments will prompt us to hold steroid therapy for a few days and perform an ACTH stimulation test. We prefer the low-dose ACTH stimulation test, where one microgram ACTH is administered intravenously, and a cortisol level is obtained at baseline and one hour after the injection. If the ACTH-stimulated cortisol exceeds 18 µg/dL, it is safe to discontinue steroid therapy. In our experience, an 8 AM cortisol over 12 µg/dL is also usually associated with recovery, and steroids may be discontinued.
If the patient’s serum cortisol exceeds 7 µg per deciliter but fails the ACTH stimulation test, we will usually transition from dexamethasone replacement to hydrocortisone 10 mg in the morning and 5 mg in the afternoon. Using the shorter-acting steroid seems to make sense in this setting and may facilitate recovery of the HPA axis.
Whenever the patient is able to successfully discontinue steroids, we recommend obtaining a baseline 24-hour urine cortisol excretion rate. We recommend repeating the 24-hour urine cortisol and a late-night salivary cortisol level at six-month intervals for 2 to 3 years and then annually after that. We usually reserve the overnight dexamethasone suppression test for patients who have a rise in urine-free cortisol or an elevated late-night salivary cortisol.
We recommend a follow-up MRI of the pituitary gland one year after surgery, even in patients thought to be in remission, to establish a reliable baseline study. The MRI need not be repeated thereafter unless there is biochemical evidence of recurrent disease.
Please contact us or refer the patient for an evaluation if you have any questions or concerns. Thank you for allowing us to participate in the care of your patient.
Nonfunctional pituitary adenoma: Successful surgery.
Your patient underwent successful surgery for a nonfunctional pituitary adenoma. The purpose of this document is to provide you with information and recommendations regarding expectant, long-term follow-up.
These benign tumors are a heterogeneous group of disorders. We usually retain patients in our practice if they have a tumor subtype that is associated with a worse prognosis or if they have residual disease requiring careful surveillance. We do not expect your patient to have an adverse outcome, but this cannot always be predicted with certainty, so follow-up is necessary.
Generally, tumor recurrences occur in 15 to 25% of patients. In our practice, the rate is about 12%. Those patients with invasive and larger tumors are more likely to have recurrences. Most recurrences occur within the first five years of surgery, but we have seen recurrences in patients delayed as long as 30 years after the initial surgery. Thus, these patients require lifetime follow-up for their pituitary condition.
We recommend pituitary protocol MRI studies with and without contrast of the sella annually for three or so years after surgery. Then, if there are no new developments, one may proceed with imaging every couple of years for a few intervals. After that, imaging studies can be obtained every five years. Any new onset visual difficulties, headaches, or pituitary hormone deficits should immediately prompt an MRI scan regardless of the schedule.
We recommend that patients with any definite or probable recurrences be referred to us for evaluation.
While some patients may be deficient in one or more anterior pituitary hormones before and after surgery, others may be normal. Regardless, all are at risk for the development of delayed hypopituitarism. We define hypopituitarism as a partial or complete deficiency of one or more anterior pituitary hormones. We see this delayed hypopituitarism occasionally and believe it’s worthwhile to check pituitary functions annually for 2 to 3 years. The cause is unknown, but new anterior pituitary hormone deficiency states have been known to herald a recurrent tumor.
We appreciate the opportunity to partner with you to manage your patients. Please do not hesitate to contact us with any questions or concerns.
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